1. Field of the Invention
The present invention relates to an excellently biocompatibile polyhydroxyalkanoate-coated liposome having a highly stable membrane, with sustained releasability of a substance encapsulated thereon being controlled, and a production method thereof.
2. Related Background Art
Liposome, which is formed when a lipid is dispersed in water, is of extremely close proximity to cell membrane structure as a model and is expected to be aggressively utilized as a medicinal substance such as a tissue-oriented drug delivery agent, artificial erythrocyte, a cell restoration agent, or an enzyme fixation base. In addition, not only in the fields of medicine and pharmacy, but also in the area of cosmetics, it is expected as a substance that selectively transports effective components having a problem in stability to an affected part and controls gradual releasability. Liposome finds an extremely wide range of applications as mentioned above, but its fragility in membrane structure has been pointed out. In other words, chemical or physical changes of a lipid, a membrane forming substance, destroy the membrane, readily causing leakage of a substance contained and drug delivery to target cells has not been sufficiently improved. Conventionally, methods of reinforcing liposome membranes are known that include a method for providing the membrane with hydrogen bonding by adding sphingomyelin thereto and reinforcing the membrane, and a method of preventing oxidation of unsaturated lipid by adding tocopherol, etc.
Furthermore, liposome with a highly stable liposome membrane and a production method thereof have been needed in order to stabilize a liposome membrane and achieve excellent drug holding therein and gradual releasability of a drug at a target cell.
Conventionally, to enhance the mechanical strength of liposome under physiological conditions and enable the membrane to control gradual releasability of a drug, Japanese Patent Application Laid-Open No. 06-178930 has proposed a liposome membrane formed by coating the surface of the membrane with a homopolymer of 2-methacryloyloxyethyl phosphorylcholine or with a copolymer of 2-methacryloyloxyethyl phosphorylcholine and a monomer.
Further, Japanese Patent Application Laid-Open No. 06-298638 has proposed liposome coated with a sterol and/or a sterol glucoside, including sitosterol, campesterol, stigmasterol, or brassicasterol.
On the other hand, as an example of formation of a capsule containing a drug therein using polyhydroxyalkanoate as a biodegradable and biocompatible substance other than phospholipid, U.S. Pat. No. 6,146,665 has disclosed a process for preparing a drug composition composed of a fine particle that has entrapped a hydrophilic drug in a porous granule made of polyhydroxyalkanoate, or a drug composition that encapsulates as the core substance an oil droplet in which a lipophilic drug is dissolved in a shell composed of polyhydroxyalkanoate.
However, the liposome formed by coating of homopolymer of 2-methacryloyloxyethyl phosphorylcholine (MPC) or of copolymer of 2-methacryloyloxyethyl phosphorylcholine and a monomer, as disclosed in Japanese Patent Application Laid-Open No. 06-178930, is definitely improved in mechanical strength, but is neither necessarily sufficient in strength nor excellent in biocompatibility.
In addition, the fine particle that entraps a hydrophilic drug in a porous granule made of polyhydroxyalkanoate, as disclosed in U.S. Pat. No. 6,146,665, is not poisonous, has biodegradability and is capable of entrapping a drug in situ; however, it allows the hydrophilic drug to immediately disperse due to its porous structure, resulting in difficulty in control of gradual releasability.